Morphine continues to be the mainstay therapy for managing intense pain. Unfortunately, some patients who initially have good pain relief lose pain control despite advancing the dose and potency of medications. Evolving tolerance, neuropathic pain and/or ascending nociceptive stimulus intensity from disease are possible explanations. Rendering a cure is the goal, but often no remedy is available. To the extent that tolerance diminished pain control, curtailment of tolerance will improve patient care. The ultimate goal of the research is to expand our understanding and improve management of uncontrollable pain syndromes. The major goals of this Scientist Development Award are: I) to develop in the nominee special skills and knowledge in the use of Positron Emission Tomography (PET) and the neuropharmacology of opioids; and 2) develop clinically relevant techniques in PET to assess neurophysiologic responses to pain and therapy. The skills acquired in the training program will be applied to protocols which test the hypotheses that pain and opiates alter neuroactivation responses measurable with PET and that dextromethorphan, an NMDA receptor antagonist, attenuates tolerance to opiates. Seventy patients naive to chronic morphine use will be recruited. Each patient will be assigned to one of two treatment groups receiving morphine with either dextromethorphan or placebo therapy. Patients will be admitted to the hospital (GCRC) for 24 hours to begin therapy and optimally titrate and establish their daily morphine dosing regimen. Upon discharge, scheduled slow release morphine and P.R.N. administered immediate release morphine will be prescribe along with the test drug/placebo. Diaries, telecommunications and clinic follow-up will be used to monitor daily pain ihtensity, side-effects and morphine use. Thirty of the seventy patients will undergo a pain activation study before and after the clinical trial to establish their neuroactivation pattern (H2-15-O bolus technique) with and without intraspinal fentanyl injection. These results will be compared to neuroactivation pain studies performed in eighteen normals before and after intraspinal fentanyl. These research activities are the perfect complement to the nominees educational plan and career objectives. The research is relevant and meaningful to patient care and provides a venue for the nominee to practice the concepts and principles gained from the tutorials and coursework. These integrated activities will allow for the development of an independent clinical scientist using PET to explore the problems of pain and the limitations of currently available analgesic medications.